Indole derivatives and drugs containing the same

ABSTRACT

An indole derivative represented by the following general formula (1):  
                 
 
wherein at least one of R 1 , R 2 , R 3 , and R 4  represents an alkoxy group containing 1 to 20 carbon atoms, and other groups of the R 1 , R 2 , R 3 , and R 4  represent hydrogen, an alkyl group containing 1 to 6 carbon atoms, acetyl group, or hydroxyl group; and either one of X and Y represents —(CH 2 ) n  OH wherein n is an integer of 0 to 30, and the other one of the X and Y represents hydrogen atom; or a salt thereof; and a drug and an agent for promoting differentiation of a stem cell containing such indole derivative or its salt as an effective component. 
The indole derivative (1) of the present invention has action of inducing differentiation of neural stem cell specifically into a neuron, and this indole derivative is useful as a prophylactic or therapeutic drug for brain dysfunction or neuropathy caused by loss or degeneration of the neuron.

TECHNICAL FIELD

This invention relates to an indole derivative which has excellentaction of inducing neuron differentiation, and which is useful as aprophylactic or therapeutic drug for brain dysfunction, neuropathy, orthe like caused by loss or injury of whole neuron including the braincell. This invention also relates to a drug containing such indolederivative as its effective component.

BACKGROUND ART

Dementia of the Alzheimer type and Parkinson's disease are braindysfunctions caused by degeneration or loss of neurons. Dementia of theAlzheimer type have been treated by using anticholinesterases ormuscarinic receptor agonist. Parkinson's disease has been treated byadministration of dopamine or dopamine agonist. Although the symptomsare temporarily improved by the treatments using such drugs, progress ofthe pathological conditions could be neither stopped nor retarded.

Motor paralysis is a disease wherein voluntary movement is inhibited bythe dysfunction of motor nerve extending from the motor center to themuscle. The motor paralysis caused by the dysfunction of the upper motornerve extending from the cerebrum to the anterior horn cell is calledcentral paralysis, and the motor paralysis caused by the dysfunction ofthe lower motor nerve extending from the anterior horn cell to muscle iscalled peripheral paralysis. Motor paralysis is divided into monoplegia(paralysis of a single limb), hemiplegia (paralysis of upper and lowerlimbs on one side of the body), paraplegia (paralysis of both lowerlimbs), and quadriplegia depending on the paralyzed part. Althoughvarious treatments (such as rehabilitation and neural transplantation)corresponding to individual symptoms have been conducted, there is sofar no therapeutic drug that is capable of regenerating the damagedneuron.

Use of a neurotrophic factor such as nerve growth factor (NGF) orbrain-derived neurotrophic factor (BDNF) for the prevention or treatmentof such diseases may be contemplated. These factors, however, arepeptides with high molecular weight, and they are easily decomposed inthe living body, and also, they are unable to pass the blood-brainbarrier. Accordingly, these factors are strictly limited in theiradministration route.

In view of the situation as described above, an object of the presentinvention is to provide a compound which has a sufficiently lowmolecular weight so that the compound can pass the blood-brain barrier,and which is capable of repairing and regenerating the degenerated orlost neurons to thereby improve various neuropathies.

DISCLOSURE OF THE INVENTION

In view of the situation as described above, the inventors of thepresent invention conducted an extensive investigation in search of alow molecular weight compound capable of inducing differentiation ofneural stem cell into the neuron, and found the indole derivativerepresented by the general formula (1) as shown below. The presentinvention has been completed on the bases of such finding.

The present invention provides an indole derivative represented by thefollowing general formula (1):

wherein at least one of R¹, R², R³, and R⁴ represents an alkoxy groupcontaining 1 to 20 carbon atoms, and other groups of the R¹, R², R³, andR⁴ represent hydrogen, an alkyl group containing 1 to 6 carbon atoms,acetyl group, or hydroxyl group; and either one of X and Y represents—(CH₂)_(n)OH wherein n is an integer of 0 to 30, and the other one ofthe X and Y represents hydrogen atom; or a salt thereof; and a drug andan agent for promoting differentiation of a stem cell containing suchindole derivative or its salt as an effective component.

This invention also provides a pharmaceutical composition containing theindole derivative represented by the above general formula (1) or a itssalt, and a pharmaceutically acceptable carrier.

This invention also provides a method for treating brain dysfunction orneuropathy wherein the indole derivative represented by the abovegeneral formula (1) or its salt is administered.

This invention also provides use of the indole derivative represented bythe above general formula (1) or its salt for producing a drug.

BEST MODE FOR CARRYING OUT THE INVENTION

The indole derivative of the present invention is the one represented bythe general formula (1). The alkoxy group represented by R¹, R², R³, orR⁴ is an alkoxy group containing 1 to 20 carbon atoms, and preferably 1to 15 carbon atoms. Examples of such alkoxy group include methoxy group,ethoxy group, and propoxy group, with more preferred being methoxygroup. Examples of the alkyl group containing 1 to 6 carbon atomsinclude methyl group, ethyl group, n-propyl group, isopropyl group, andbutyl group.

With regard to X or Y, n is a number of 0 to 30, more preferably 1 to20.

The indole derivative (1) of the present invention is preferably the onewherein at least one of R¹, R², R³, and R⁴ is an alkoxy group containing1 to 10 carbon atom, and the remainder of the R¹, R², R³, and R⁴ ishydrogen atom, and n in X or Y is 10 to 20.

Of the indole derivatives (1) of the present invention, the one whereinX is —(CH₂)_(n)OH, and Y is hydrogen atom may be produced by thereaction scheme as shown below.

More specifically, an alkoxybenzaldehyde is reacted with methyl azideacetate to produce azide ester (2). This azide ester (2) is dissolved inxylene, and refluxed to produce indole carboxylic acid ester (3). Thisindole carboxylic acid ester (3) is added to aqueous solution of sodiumhydroxide, and the solution was refluxed to produce indole carboxylicacid (4), and this indole carboxylic acid (4) is refluxed in thepresence of copper powder and quinoline to produce alkoxy indole (5). Tothis alkoxy indole (5) is added N,N-dimethylformamide and sodiumpyrophosphate, and the solution is refluxed to produce aldehyde (6).This aldehyde (6) is reacted with alkoxybenzene sulfonylchloride toproduce aldehyde (7), and this aldehyde (7) is reacted with benzyloxyalkyltriphenyl phosphonium bromide to produce alkene (8). The alkane (8)is hydrogenated to produce compound (9), and this compound (9) isdesulfonated to produce indole derivative (1-1).

Of the indole derivative (1) of the present invention, the one wherein Xis hydrogen atom and Y is —(CH₂)_(n)OH may be produced by the followingreaction scheme.

More specifically, hydroxyl group of a bromo-ω-alkanol (11) is protectedwith silyl group (TBDMSCl), and the bromo-group is substituted by usinglithium acetylide to produce alkyne (13). In the meanwhile, aniline (14)is protected with tert-butyl carbamic acid, and iodized to produceiodized aromatic carbarmate ester (16). Next, the resulting iodizedaromatic carbarmate ester (16) and the alkyne (13) are allowed toundergo Sonogashira coupling by using Pd(PPh₃)₄, CuI, and Et₃N toproduce aromatic carbamic acid derivative (17). The protective group onthe hydroxyl group is then removed and the amino group moiety iscyclized to produce indole derivative (1-2). In this reaction, 15equivalents of tetrabutylammonium fluoride is required, and the reactiontime (24 to 48 hours) may vary depending on the reactivity of theaniline employed.

The intermediates produced in various steps of the reaction as describedabove and the resulting indole derivative (1) may be isolated andpurified by a method commonly used for the purification in the syntheticorganic chemistry, for example, filtration, extraction, washing, drying,concentration, recrystallization, and various chromatographic processes.The intermediates, however, may be used in the subsequent step with nofurther purification.

The indole derivative (1) of the present invention may be in the form ofa pharmaceutically acceptable salt, a solvate or a hydrate thereof. Thecompound may also be one of various isomers of the compound, and all ofsuch isomers are within the scope of the present invention.

The salt of the indole derivative (1) may be an alkaline metal salt suchas sodium, potassium, or lithium salt or an alkaline earth metal saltsuch as magnesium or calcium salt.

The thus produced indole derivative (1) or its salt of the presentinvention has action of inducing differentiation of neural stem cellspecifically into neuron, and therefore, this indole derivative isuseful as a drug such as a prophylactic or therapeutic drug for braindysfunction (such as dementia of the Alzheimer type or Parkinson'sdisease) and neuropathy (such as motor paralysis) caused by neuron lossor degeneration or as a promoter for stem cell differentiation.

The drug of the present invention contains the indole derivative (1) orits salt as its effective component, and this derivative (1) and itssalt has a low molecular weight. Therefore, the drug can be administeredby either by oral administration or perenteral administration (such asintramuscular, subcutaneous, venous or suppository administration).

In producing an oral preparation, the drug of the present invention maybe combined with an excipient, and if desired, further with a binder, adisintegrant, a lubricant, a colorant, a corrective, or the like, andproduced into a tablet, a coated tablet, granules, a capsule, asolution, a syrup, an elixir, an oil-base or water-base suspension, orthe like by a method commonly used in the art.

Exemplary excipients include lactose, corn starch, white sugar, glucose,sorbite, and crystalline cellulose, and exemplary binders includepolyvinyl alcohol, polyvinyl ether, ethylcellulose methylcellulose,gumarabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,hydroxypropyl starch, and polyvinyl pyrrolidone.

Exemplary disintegrants include starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextran, and pectin, and exemplary lubricants includemagnesium stearate, talc, polyethylene glycol, silica, and hardenedvegetable oil. Exemplary colorants are those approved for use in thedrugs, and exemplary correctives include cocoa powder, peppermintcamphor, aromatic acid, peppermint oil, borneol, and cinnamon powder.The tablets and the granules may be provided with an optional coatingsuch as sugar coating and gelatin coating.

In producing a parenteral preparation, the drug of the present inventionmay be combined with a pH adjusting agent, a buffer, a preservative, orother additives as desired, and produced into the desired preparation bya method commonly used in the art. The solution prepared may be placedin a vessel and produced into a solid preparation, for example, byfreeze-drying, and in this case, the solid preparation may be preparedinto the desired dosage form immediately before its use. In this case,the solution placed in the vessel may be either the solution of theamount corresponding to a single dose or multiple doses.

The drug of the present invention may be administered at differentamount depending on the patient's body weight, age, sex, symptoms, andthe like. Typical dose in the case of an adult is 0.001 to 3000 mg, andin particular, 0.01 to 1000 mg per day of the compound represented bythe general formula (1), and this dose may be administered as a singledose or in several doses.

EXAMPLES

Next, the present invention is described in further detail by referringto the Examples which by no means limit the scope of the presentinvention.

Example 1 (1-1) Production of methyl2-azide-3-(2-methoxyphenyl)-acrylate (2a)

A solution of sodium methoxide (30% w/w, 22 mL, 0.12 mol, 4 eq) inmethanol (40 mL) was cooled to −10° C. A mixture of2-methoxybenzaldehyde (4 g, 29.38 mmol, 1 eq) and methyl azide acetate(13.5 g, 0.12 mmol, 4 eq) with methanol (10 mL) was added dropwise tothis solution for 1.5 hours. The mixture was stirred for another 1.5hours at −10° C., poured into ice water (100 mL), and extracted threetimes with ethyl ether (100 mL). The extracts were combined, washed withaqueous solution of sodium chloride, dried over magnesium sulfate, andconcentrated. The concentrate was subjected to silica gel flushchromatography using hexane-ethyl acetate (90-10) to give yellow solidof the title compound (2a) (4.66 g, yield 68%).

TLC: (hexane-AcOEt: 8-2) Rf=0.51

¹H NMR (300 M Hz), δ: 3.87 (s, 3H, H-11), 3.91 (s, 3H, H-10), 6.89 (d,J=7.9 Hz, 1H, H-6), 6.99 (t, J=7.7 Hz, 1H, H-8), 7.32(dt, J=7.9 Hz,J=1.5 Hz, 1H, H-7), 7.40(s, 1H, H-3), 8.19(dd, J=7.7 Hz, J=1.5 Hz, 1H,H-9).

¹³C NMR (75 M Hz), δ: 52.81 (C-10), 55.57 (C-11), 110.44 (C-6), 119.64,120.35 (C-3, 8), 122.02 (C-4), 125.05 (C-2), 130.56, 130.85 (C-7, 9),157.56(C-5), 164.23(C-1).

(1-2) methyl 2-azide-3-(3-methoxyphenyl)-acrylate (2b)

The title compound (2b) was obtained by a procedure similar to (1-1)(yield 45%).

TLC: (hexane-AcOEt: 8-2) Rf=0.53

¹H NMR (300 M Hz), δ: 3.84(s, 3H, H-11), 3.91(s, 3H, H-10), 6.89(s, 1H,H-3), 6.92(m, 1H, H-7), 7.30(s, 1H, H-5), 7.33(m, 1H, H-9), 7.43(m, 1H,H-8)

¹³C NMR (75 M Hz), δ: 52.91(C-10), 55.29(C-11), 115.34, 115.48(C-5, 7),123.40(C-9), 125.43(C-3), 125.53(C-2), 129.39(C-8), 134.34(C-4),159.44(C-6), 163.96(C-1).

(1-3) Production of methyl 2-azide-3-(4-methoxyphenyl)-acrylate (2c)

The title compound (2c) was obtained by a procedure similar to (1-1)(yield 72%).

TLC: (hexane-AcOEt: 8-2) Rf=0.51

¹H NMR (300 M Hz), δ: 3.84(s, 3H, H-11), 3.89(s, 3H, H-10), 6.89(s, 1H,H-3), 6.91(d, J=9.1 Hz, 1H, H-5,9), 7.79(d, J=9.1 Hz, 1H, H-6,8).

¹³C NMR (75 MHz), δ: 52.73(C-10), 55.31(C-11), 113.92(C-6, 8),123.07(C-4), 125.69(C-3), 125.96(C-2), 132.39(C-5, 9), 160.50(C-5),164.25(C-1).

(2-1) Production of methyl 4-methoxy-1H-indole-2-carboxylate (3a)

The azide ester (2a) (3.7 g, 15.86 mmol, 1 eq) obtained in (1-1) wasdissolved in 250 mL of xylene in argon atmosphere. The solution wasrefluxed for 1 hour, and the solvent was evaporated under reducedpressure. The resulting solid was subjected to silica gel flushchromatography using hexane-ethyl acetate (80-20) to give white solid ofthe title compound (3a) (2.85 g, yield 88%).

TLC: (hexane-AcOEt: 8-2) Rf=0.26

¹H NMR (300 M Hz), δ: 3.95(s, 3H, H-9), 3.96(s, 3H, H-10), 6.51(d, J=8.1Hz, 1H, H-5), 7.03(d, J=8.1 Hz, 1H, H-7), 7.24(t, J=8.1 Hz, 1H, H-6),7.36(s, 1H, H-3), 9.17(s, 1H, H-1).

³C NMR (75 M Hz), δ: 51.95(C-9), 55.32(C-10), 99.74(C-5), 104.84(C-7),106.51(C-3), 118.96(C-3′), 125.78(C-2), 126.45(C-6), 138.31(C-7′),154.61(C-4), 162.51(C-8).

(2-2) Production of methyl 5-methoxy-1H-indole-2-carboxylate (3b)

The title compound (3b) was obtained by a procedure similar to (2-1)(yield 34%).

TLC: (hexane-CH₂Cl₂: 5-5) Rf=0.11 ¹H NMR (300 M Hz), δ: 3.85(s, 3H,H-10), 3.94(s, 3H, H-9), 7.00(dd, J=8.9 Hz, J=2.2 Hz, 1H, H-6), 7.08(d,J=2.2 Hz, 1H, H-4), 7.14(s, 1H, H-3), 7.32(d, J=8.9 Hz, 1H, H-7),8.91(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 51.94(C-9), 55.66(C-10), 102.52(C-4), 108.32(C-3),112.75(C-6), 117.09(C-7), 127.47(C-2), 127.81(C-3′), 132.21(C-7′),154.72(C-5), 162.35(C-8).

(2-3) Production of methyl 6-methoxy-1H-indole-2-carboxylate (3c)

The title compound (3c) was obtained by a procedure similar to (2-1)(yield 94%).

TLC: (hexane-AcOEt: 8-2) Rf=0.19

¹H NMR (300 M Hz), δ: 3.85(s, 3H, H-9), 3.94(s, 3H, H-10), 6.83(dd,J=9.5 Hz, J=2.2 Hz, 1H, H-5), 6.84(s, 1H, H-3), 7.17(d, J=2.2 Hz, 1H,H-7), 7.55(d, J=9.5 Hz, 1H, H-4), 9.02(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 51.83(C-9), 55.45(C-10), 93.71(C-7), 109.18(C-3),112.34(C-5), 121.81(C-3′), 123.38(C-4), 125.99(C-2), 138.03(C-7′),158.90(C-6), 162.50(C-8).

(2-4) Production of methyl 7-methoxy-1H-indole-2-carboxylate (3d)

The title compound (3d) was obtained by a procedure similar to (2-1)(yield 27%).

TLC: (hexane-CH₂Cl₂: 5-5) Rf=0.30

¹H NMR (300 M Hz), δ: 3.95(s, 3H, H-9), 3.98(s, 3H, H-10), 6.74(d, J=7.9Hz, 1H, H-6), 7.08(t, J=7.9 Hz, 1H, H-5), 7.21(s, 1H, H-3), 7.29(d,J=7.9 Hz, 1H, H-4), 9.09(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 52.05(C-9), 55.50(C-10), 104.24 (C-6),109.05(C-3), 114.89(C-5), 121.31(C-4), 126.93(C-7′), 128.23(C-3′),128.71(C-2), 146.58(C-7), 162.32(C-8).

(3-1) Production of 4-methoxy-1H-indole-2-carboxylic acid (4a)

The carboxylate (3a) (4 g, 19.49 mmol, 1 eq) obtained in (2-1) was addedto aqueous solution of sodium hydroxide (2M, 98 mL, 0.20 mmol, 10 eq).The suspension was stirred and heated until the reaction mixture wasuniform, and then refluxed for 30 minutes with heating. The mixturesolution was acidified, and the resulting precipitate was extractedthree times with ethyl acetate (100 mL). The extracts were combined,washed with water, dried over magnesium sulfate, and concentrated togive white solid of the title compound (4a) (3.71 g, yield 99%). ¹H NMR(300 M Hz), δ: 3.91(s, 3H, H-9), 6.55 (d, J=7.9 Hz, 1H, H-5) 7.06(d,J=7.9 Hz, 1H, H-7), 7.09(s, 1H, H-3), 7.19(t, J=7.9 Hz, 1H, H-6),11.79(s, 1H, H-1), 12.87(s, 1H, H-8).

¹³C NMR (75 M Hz), δ: 55.40(C-9), 99.67(C-5), 104.87, 105.83(C-3,7),118.38(C-3′), 125.76(C-6), 127.42(C-2), 138.92(C-7′), 154.09(C-4),162.97(C-8).

(3-2) Production of 5-methoxy-1H-indole-2-carboxylic acid (4b)

The title compound (4b) was obtained by a procedure similar to (3-1)(yield 99%).

¹H NMR (300 M Hz), δ: 3.79(s, 3H, H-9), 6.93(dd, J=8.9 Hz, J=2.2 Hz, 1H,H-6), 7.03(s, 1H, H-3), 7.13(d, J=2.2 Hz, 1H, H-4), 7.36(d, J=8.9 Hz,1H, H-7), 11.64(s, 1H, H-8), 12.86(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 55.12(C-9), 101.89(C-4), 106.84(C-3), 113.26(C-6),115.70(C-7), 127.06(C-2), 128.52(C-3′), 132.48(C-7′), 153.73(C-4),162.65(C-8).

(3-3) Production of 6-methoxy-1H-indole-2-carboxylic acid (4c)

The title compound (4c) was obtained by a procedure similar to (3-1)(yield 99%).

¹H NMR (300 M Hz), δ: 3.81(s, 3H, H-9), 6.75(dd, J=8.8 Hz, J=1.9 Hz, 1H,H-5), 6.90(s, 1H, H-3), 7.05(d, J=1.9 Hz, 1H, H-7), 7.55(d, J=8.8 Hz,1H, H-4), 11.58(s, 1H, H-1), 12.73(s, 1H, H-8).

¹³C NMR (75 M Hz), δ: 55.00(C-9), 93.85(C-7), 107.70(C-3), 111.48(C-5),121.10(C-3′), 122.68(C-4), 127.09(C-2), 138.22(C-7′), 157.60(C-6),162.62(C-8).

(3-4) Production of 7-methoxy-1H-indole-2-carboxylic acid (4d)

The title compound (4d) was obtained by a procedure similar to (3-1)(yield 96%).

¹H NMR (300 M Hz), δ: 3.94(s, 3H, H-9), 6.80 (d, J=7.8 Hz, 1H, H-6)7.02(d, J=7.8 Hz, 1H, H-5), 7.11(s, 1H, H-3), 7.25(d, J=7.8 Hz, 1H,H-3), 11.65(s, 1H, H-8), 12.82(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 56.24(C-9), 105.02(C-6), 109.09(C-3), 115.12(C-5),121.55(C-4), 129.06, 129.24, 129.53(C-2,3′,7′), 147.65(C-7),163.46(C-8).

(4-1) Production of 4-methoxy-1H-indole (5a)

The carboxylic acid (4a) (3.65 g, 19.09 mmol, 1 eq), copper powder (849mg, 13.36 mmol, 0.7 eq) obtained in (3-1) and freshly distilledquinoline (5 mL) were refluxed for2hours. The mixture was then cooled,and filtered through a celite filter. The filtrate was poured into ice,and the solution was adjusted to pH 4 with conc. hydrochloric acid, andthe solution was extracted three times with ethyl acetate (100 mL). Theextracts were combined and washed three times with 2M hydrochloric acid(100 mL), further with saturated sodium hydrogen carbonate, and stillfurther with aqueous solution of sodium chloride. The organic solutionwas dried over magnesium sulfate, and concentrated. The resultingconcentrate was subjected to silica gel flush chromatography usinghexane-ethyl acetate (85-15) to give white solid of the title compound(5a) (2.64 g, yield 94%).

TLC: (hexane-AcOEt: 8-2) Rf=0.4

¹H NMR (300 M Hz), δ: 3.99(s, 3H, H-8), 6.57(d, J=7.9 Hz, 1H, H-5),6.70(t, J=2.5 Hz, 1H, H-3), 7.03(t, J=7.9 Hz, 1H, H-7), 7.10(t, J=2.5Hz, 1H, H-2), 7.16(t, J=7.9 Hz, 1H, H-6), 8.13(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 53.34(C-8), 99.59, 99.79(C-3,5), 104.52(C-7),118.56(C-3′), 122.73, 122.78(C-2,6), 137.25(C-7′), 153.39(C-4).

(4-2) Production of 5-methoxy-1H-indole (5b)

The title compound (5b) was obtained by a procedure similar to (4-1)(yield 77%).

TLC: (hexane-AcOEt: 8-2) Rf=0.39

¹H NMR (300 M Hz), δ: 3.87(s, 3H, H-8), 6.50(t, J=2,8 Hz, 1H, H-3),6.89(dd, J=8.8 Hz, J=2.4 Hz, 1H, H-6), 7.13(d, J=2.4 Hz, 1H, H-4),7.19(t, J=2.8 Hz, 1H, H-2), 7.28 (d, J=8.8 Hz, 1H, H-7), 8.06(s, 1H,H-1).

¹³C NMR (75 M Hz), δ: 55.86(C-8), 102.34, 102.37(C-3, 6), 111.70(C-4),112.35(C-7), 124.87(C-2), 130.12(C-3′), 130.97(C-7′), 154.20(C-5).

(4-3) Production of 6-methoxy-1H-indole (5c)

The title compound (5c) was obtained by a procedure similar to (4-1)(yield 87%).

TLC: (hexane-AcOEt: 8-2) Rf=0.38

¹H NMR (300 M Hz), δ: 3.87(s, 3H, H-8), 6.52(d, J=2.6 Hz, 1H, H-3),6.85(m, 2H, H-5, 7), 7.08(t, J=2.6 Hz, 1H, H-2), 7.55(d, J=9.1 Hz, 1H,H-4), 7.99(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 55.68(C-8), 94.57(C-7), 102.39(C-3), 109.91(C-5),121.26(C-4), 122.15(C-3′), 123.09(C-2), 136.55(C-7′), 156.40(C-6).

(4-4) Production of 7-methoxy-1H-indole (5d)

The title compound (5d) was obtained by a procedure similar to (4-1)(yield 66%).

TLC: (hexane-AcOEt: 8-2) Rf=0.45

¹H NMR (300 M Hz), δ: 3.98(s, 3H, H-8), 6.56(t, J=2.7 Hz, 1H, H-3),6.67(d, J=-7.7 Hz, 1H, H-6), 7.06(t, J=7.7 Hz, 1H, H-5), 7.19(t, J=2.7Hz, 1H, H-2), 7.29(d, J=7.7 Hz, 1H, H-4), 8.39(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 57.63(C-8), 104.04(C-6), 105.21(C-3), 115.76(C-5),122.47(C-4), 125.98(C-2), 128.79(C-3′), 131.52(C-7′), 148.52(C-7).

(5-1) Production of 4-methoxy-1H-indole-3-carbaldehyde (6a)

A mixture of the indole (5a) (1.7 g, 11.55 mmol, 1 eq) obtained in (4-1)and N,N-dimethylformamide (4.5 mL, 57.76 mmol, 5 eq) was stirred at 0°C., and sodium pyrophosphate (1.9 mL, 13.86 mmol, 1.2 eq) was addeddropwise to this mixture. The resulting solution was stirred at 0° C.for 0.5 hour, and then, at 40° C. for 1 hour. Ice, and then, aqueoussolution of sodium hydroxide (2M) was added, and the mixture was heatedunder reflux. The solution was extracted three times with ethyl acetate(50 mL). The extracts were combined, washed with aqueous solution ofsodium chloride, dried over magnesium sulfate, and concentrated. Theconcentrate was subjected to silica gel flush chromatography usinghexane-ethyl acetate (60-40) to give white solid of the title compound(6a) (1.72 g, yield 85%).

TLC: (hexane-AcOEt: 6-4) Rf=0.24

¹H NMR (300 M Hz), δ: 4.00(s, 3H, H-9), 6.72(d, J=8.1 Hz, 1H, H-5),7.09(d, J=8.1 Hz, 1H, H-7), 7.21 (t, J=8.1 Hz, 1H, H-6), 7.92 (d, J=3.1Hz, 1H, H-2), 9.36(s, 1H, H-1), 10.50(s, 1H, H-8).

¹³C NMR (75 M Hz), δ: 55.24(C-9), 102.18(C-5), 105.74(C-7), 115.49(C-3),118.03(C-3′), 123.46(C-6), 129.53(C-2), 137.82(C-7′), 153.75(C-4),186.24(C-8).

(5-2) Production of 5-methoxy-1H-indole-3-carbaldehyde (6b)

The title compound (6b) was obtained by a procedure similar to (5-1)(yield 90%).

TLC: (hexane-AcOEt: 5-5) Rf=0.30

¹H NMR (200 M Hz), δ: 3.83(s, 3H, H-9), 6.92(dd, J=8.9 Hz, J=2.5 Hz, 1H,H-6), 7.44(d, J=8.9 Hz, 1H, H-7), 7.63(d, J=2.5 Hz, 1H, H-4), 8.25(s,1H, H-2), 9.93(s, 1H, H-8), 12.06(s, 1H, H-1).

¹³C NMR (50 M Hz), δ: 55.22 (C-9), 102.46(C-4), 113.10, 113.19(C-6,7),117.97(C-3), 124.82(C-3′), 131.73(C-7′), 138.29(C-2), 155.57(C-5),184.72(C-8).

(5-3) Production of 6-methoxy-1H-indole-3-carbaldehyde (6c)

The title compound (6c) was obtained by a procedure similar to (5-1)(yield 89%).

TLC: (hexane-AcOEt: 6-4) Rf=0.14

¹H NMR (300 M Hz), δ: 3.82(s, 3H, H-9), 6.85(dd, J=8.6 Hz, J=2.2 Hz, 1H,H-5), 6.99(d, J=2.2 Hz, 1H, H-7), 7.98(d, J=8.6 Hz, 1H, H-4), 8.05(s,1H, H-2), 9.89(s, 1H, H-8), 12.08(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 55.03(C-9), 95.24(C-7), 111.56(C-5), 117.94,118.24(C-3, 3′), 121.34(C-4), 137.00(C-2), 137.92(C-7′), 156.66(C-6),184.25(C-8)

(6-1) Production of4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-carbaldehyde (7a)

To the solution of the compound (6a) (1.68 g, 9.59 mmol, 1 eq) obtainedin (5-1) in dichloromethane (20 mL) was added pellets of sodiumhydroxide (574 mg, 14.34 mmol, 1.5 eq), and the mixture was stirred atroom temperature for 30 minutes.

4-methoxybenzsulfonyl chloride (2.96 g, 14.34 mmol, 1.5 eq) was thenadded, and the mixture was stirred at room temperature for 12 hours.Ammonium chloride (100 mL) was then added, and the solution wasextracted three times with ethyl acetate (100 mL). The extracts werecombined, washed with aqueous solution of sodium chloride, dried overmagnesium sulfate, and concentrated. The resulting concentrate wassubjected to silica gel flush chromatography using hexane-ethyl acetate(70-30) to give white solid of the title compound (7a) (3.15 g, yield97%).

TLC: (hexane-AcOEt: 6-4) Rf=0.45

¹H NMR (300 M Hz), δ: 3.84(s, 3H, H-9), 3.95(s, 3H, H-10), 6.99(d, J=8.2Hz, 1H, H-5), 7.15(d, J=9.0 Hz, 2H, H-3″,5″), 7.41(t, J=8.2 Hz, 1H,H-6), 7.61(d, J=8.2 Hz, 1H, H-7), 8.12(d, J=9.0 Hz, 2H, H-2−,6″),8.40(s, 1H, H-2), 10.40(s, 1H, H-8).

¹³C NMR (75 M Hz), δ: 55.71, 55,90(C-9,10), 105.47, 105.97(C-5,7),115.21(C-3″,5″), 116.43(C-3′), 121.43(C-3), 126.82(C-6), 127.20(C-7′),129.14(C-2), 129.86(C-2″,6″), 135.28(C-1″), 153.88(C-4), 164.32(C-4″),186.98(C-8).

(6-2) Production of5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-carbaldehyde (7b)

The title compound (7b) was obtained by a procedure similar to (6-1)(yield 95%).

TLC: (hexane-AcOEt: 5-5) Rf=0.57

¹H NMR (300 M Hz), δ: 3.81(s, 3H, H-9), 3.84(s, 3H, H-10), 6.93(d, J=8.9Hz, 2H, H-3″,5″), 6.99(dd, J=9.1 Hz, J=2.5 Hz, 1H, H-6), 7.71(d, J=2.5Hz, 1H, H-4), 7.81(d, J=9.1 Hz, 1H, H-7), 7.88(d, J=8.9 Hz, 2H,H-2″,6″), 8.17(s, 1H, H-2), 10.05(s, 1H, H-8).

¹³C NMR (75 M Hz), δ: 55.82 (C-9,10), 104.12 (C-4), 114.14 (C-6),114.94(C-3″,5″), 116.16(C-7), 122.21(C-3), 127.40(C-3′), 128.70(C-7′),129.57(C-2″,6″), 135.23(C-1″), 136.69(C-2), 157.80(C-5), 164.51(C-4″),185.51(C-8).

(6-3) Production of6-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-carbaldehyde (7c)

The title compound (7c) was obtained by a procedure similar to (G-1)(yield 97%).

TLC: (hexane-AcOEt: 6-4) Rf=0.39

¹H NMR (300 M Hz), δ: 3.85(s, 3H, H-9), 3.99(s, 3H, H-10), 7.07(dd,J=8.8 Hz, J=2.2 Hz, 1H, H-5), 7.18(d, J=8.9 Hz, 2H, H-3″,5″), 7.44(d,J=2.2 Hz, 1H, H-7), 8.01(d, J=8.8 Hz, 1H, H-4), 8.10(d, J=8.9 Hz, 2H,H-2″,6″), 8.77(s, 1H, H-2), 10.05(s, 1H, H-8).

¹³C NMR (75 M Hz), δ: 55.55, 55.88(C-9,10), 97.23(C-7), 113.53(C-5),115.32(C-3″,5″), 119.12(C-3′), 121.48(C-3), 122.41(C-4), 127.23(C-7′),129.69(C-2″,6″), 135.42(C-1″), 137.32(C-2), 158.21(C-6), 164.30(C-4″),186.53(C-8).

(7-1) Production of 3-(10-benzyloxy1-decenyl)-4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole (8a, n=10)

A solution of nBuLi in hexane (1.5M, 0.7 mL, 1.04 mmol, 1.2 eq) wasadded dropwise to a solution of 9-benzyloxy-nonyltriphenylphosphoniumbromide (600 mg, 1.04 mmol, 1.2 eq) in THF (12 mL) at −78° C. in argonatmosphere. The solution was stirred at room temperature for 15 minutes,and tert-butoxy potassium (117 mg, 1.04 mmol, 1.2 eq) was added at 0° C.The solution was stirred at 0° C. for 15 minutes. The solution was thencooled to −78° C., and to the solution was gradually added a solution ofaldehyde (7a) obtained in (6-1) (300 mg, 0.87 mmol, 1 eq) in THF (7 mL).The solution was stirred at −78° C. for 1 hour, and then, at 0° C. for1.5 hours. The mixed solution was poured into saturated ammoniumchloride solution (50 mL), and the solution was extracted three timeswith ethyl ether (50 mL). The organic phase was combined, washed withaqueous solution of sodium chloride, dried over magnesium sulfate, andconcentrated. The resulting concentrate was applied to silica gel usinghexane-ethyl acetate (90-10) to (85-15) for the eluate to give whitesolid of the title compound (8a, n=10) (362 mg, yield 74%).

TLC: (hexane-AcOEt: 8-2) Rf=0.40

¹H NMR (300 M Hz), δ: 1.33(s br, 8H, H-12 to 15), 1.47(m, 2H, H-16),1.62(m, 2H, H-11), 2.32(q, J=6.9 Hz, 2H, H-10), 3.47(t, J=6.9 Hz, 2H,H-17), 3.77(s, 3H, H-19), 3.86(s, 3H, H-20), 4.51(s, 2H, H-18), 5.70(dt,J=10.6 Hz, J=6.9 Hz, 1H, H-9), 6.63(d, J=7.8 Hz, 1H, H-5), 6.80(d,J=10.6 Hz, 1H, H-8), 6.86(d, J=8.9 Hz, 2H, H-3″,5″), 7.16-7.37(m, 6H,H-7, H-2′″ to 6′″), 7.38(s, 1H, H-2), 7.58(t, J=7.8 Hz, 1H, H-6),7.80(d, J=8.9 Hz, 2H, H-2″,6″).

¹³C NMR (75 M Hz), δ: 26.16(C-10), 29.18-29.76(C-11 to 16), 55.36, 55.58(C-19,20), 70.49(C-17), 72.84(C-18), 103.87, 104.05 (C-3, 5),106.57(C-7), 114.36(C-3″,5″), 119.47(C-3′), 120.53(C-2), 122. 46(C-6),125.58(C-8), 127.43(C-4′″), 127.60(C-2′″,6′″), 128.31(C-2″,6″),129.01(C-3′″,5′″), 131.69(C-1″), 132.71(C-9), 136.56(C-7′),138.71(C-1′″), 154.87(C-4), 163.65(C-4″)

(7-2) Production of 3-(10-benzyloxy1-decenyl)-5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole (8b, n=10)

White solid of the title compound (8b, n=10) was obtained by a proceduresimilar to (7-1) (yield 65%).

TLC: (hexane-AcOEt: 7-3) Rf=0.49

¹H NMR (200 M Hz), δ: 1.31 (s br, 8H, H-12 to 15), 1.48 (m, 2H, H-16),1.61(m, 2H, H-11), 2.30(q, J=6.9 Hz, 2H, H-10), 3.46(t, J=6.4 Hz, 2H,H-17), 3.77(s, 3H, H-19), 3.82(s, 3H, H-20), 4.50(s, 2H, H-18), 5.80(dt,J=11.3 Hz, J=6.9 Hz, 1H, H-9), 6.34(d, J=11.3 Hz, 1H, H-8), 6.85(d,J=8.9 Hz, 2H, H-3″,5″), 6.89-6.94(m, 2H, H-4, 6), 7.33(m, 5H, H-2′″ to6′″), 7.45(s, 1H, H-2), 7.78 (d, J=8.9 Hz, 2H, H-2″,6″), 7.87(d, J=9.6Hz, 1H, H-7).

¹³C NMR (50 M Hz), δ: 26.24(C-10), 29.52-29.82(C-11 to 16),55.71(C-19,20), 70.56(C-17), 72.92(C-18), 102.03(C-4), 113.91(C-6),114.43(C-3″,5″), 114.60(C-3), 117.55(C-7), 119.42(C-3′), 124.33(C-2),127.51(C-8), 127.68(C-2′″,6′″), 128.39(C-3′″,5′″), 128.99(C-2″,6″),129.23(C-4′″), 129.60(C-7′), 131.86(C-1″), 134.85(C-9), 138.53(C-1′″),156.35(C-5), 163.73(C-4″).

(7-3) Production of 3-(10-benzyloxy1-decenyl)-6-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole (8c, n=10)

White solid of the title compound (8c, n=10) was obtained by a proceduresimilar to (7-1) (yield 91%).

TLC: (hexane-AcOEt: 8-2) Rf=0.32

¹H NMR (300 M Hz), δ: 1.31(s br, 8H, H-12 to 15), 1.48(m, 2H, H-16),1.61(m, 2H, H-11), 2.30(q, J=6.7 Hz, 2H, H-10), 3.46(t, J=6.6 Hz, 2H,H-17), 3.78(s, 3H, H-19), 3.88(s, 3H, H-20), 4.50(s, 2H, H-18), 5.79(dt,J=11.5 Hz, J=6.7 Hz, 1H, H-9), 6.35(d, J=11.5 Hz, 1H, H-8), 6.87(d,J=8.9 Hz, 2H, H-3″,5″), 6.88(m, 1H, H-5), 7.33(m, 6H, H-4, H-2′″ to6′″), 7.39(s, 1H, H-2), 7.52(d, J=2.0 Hz, 1H, H-7), 7.80(d, J=8.9 Hz,2H, H-2″,6″).

¹³C NMR (75 M Hz), δ: 26.15(C-10), 29.31-29.75(C-11 to 16), 55.59,55.79(C-19,20), 70.48(C-17), 72.84(C-18), 97.92(C-7), 112.25(C-5),114.39(C-3″,5″), 117.54(C-4), 119.23(C-3), 120.02 (C-2), 122.16 (C-8),124.73 (C-3′), 127.43-128.92 (C-2″,6″, C-2′″ to 6′″), 129.64(C-1″),134.73(C-9), 135.60(C-7′), 138.71(C-1′″), 158.09(C-5), 163.70(C-4¹¹).

(7-4)

The following compounds were produced by procedures similar to (7-1).The yield is shown in Table 1.

-   -   3-(12-benzyloxy        1-dodecenyl)-4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole (8a,        n=12),    -   3-(14-benzyloxy        1-tetradecenyl)-4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indol e        (8a, n=14),    -   3-(16-benzyloxy        1-hexadecenyl)-4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole        (8a, n=16),    -   3-(18-benzyloxy        1-octadecenyl)-4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole        (8a, n=18),    -   3-(12-benzyloxy        1-dodecenyl)-5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole (8b,        n=12),    -   3-(14-benzyloxy        1-tetradecenyl)-5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indol e        (8b, n=14),    -   3-(16-benzyloxy        1-hexadecenyl)-5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole        (8b, n=16),    -   3-(18-benzyloxy        1-octadecenyl)-5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole        (8b, n=18),

3-(12-benzyloxy1-dodecenyl)-6methoxy-1-(4-methoxybenzsulfonyl)-1H-indole (8c, n=12)TABLE 1 X = —(CH₂)_(n)OH R n Formula MW Yield 8a 4-MeO 10 C₃₃H₃₉NO₅S561.73 74% 12 C₃₅H₄₃NO₅S 589.79 71% 14 C₃₇H₄₇NO₅S 617.84 45% 16C₃₉H₅₁NO₅S 645.89 69% 18 C₄₁H₅₅NO₅S 673.95 68% 8b 5-MeO 10 C₃₃H₃₉NO₅S561.73 65% 12 C₃₅H₄₃NO₅S 589.79 62% 14 C₃₇H₄₇NO₅S 617.84 84% 16C₃₉H₅₁NO₅S 645.89 94% 18 C₄₁H₅₅NO₅S 673.95 71% 8c 6-MeO 10 C₃₃H₃₉NO₅S561.73 91% 12 C₃₅H₄₃NO₅S 589.79 78%

(8-1) Production of10-(4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-deca ne-1-ol(9a, n=10)

Pd—C (5%, 35 mg, 10 mol %) was added to solution of the alkene obtainedin (7-1) (8a, n=10) (350 mg, 0.62 mmol, 1 eq) in ethanol (6 mL). Themixed solution was stirred at room temperature in hydrogen atmosphere of1 atm. for 4 hours. The mixture was then filtered through celite, andconcentrated. The resulting concentrate was subjected to silica gelflush column chromatography using hexane-ethyl acetate (70-30) to givewhite solid of the title compound (9a, n=10) (277 mg, yield 93%).

TLC: (hexane-AcOEt: 7-3) Rf=0.13

¹H NMR (300 M Hz), δ: 1.27(s br, 12H, H-10 to 15), 1.59 (m, 4H, H-9,16),2.76(t, J=7.3 Hz, 2H, H-8), 3.64(t, J=6.2 Hz, 2H, H-17), 3.78(s, 3H,H-18), 3.85(s, 3H, H-19), 6.61(d, J=8.2 Hz, 1H, H-5), 6.85(d, J=8.9 Hz,2H, H-3″,5″), 7.15(s, 1H, H-2), 7.18(t, J=8.2 Hz, 1H, H-6), 7.56(d,J=8.2 Hz, 1H, H-7), 7.77(d, J=8.9 Hz, 2H, H-2″,6″).

¹³C NMR (75 M Hz), δ: 25.72(C-15S), 26.85(C-9), 29.34-29.80(C-8,10 to14), 32.79(C-16), 55.18, 55.55(C-18,19), 63.09(C-17), 103.55(C-5),106.62(C-7), 114.25(C-3″,5″), 120.59(C-3), 121.24(C-6), 124.10(C-3′),125.27(C-2), 128.93(C-2″,6″), 129.83(C-1″), 136.95(C-7′), 154.62(C-4),163.50(C-4″).

(8-2) Production of10-[5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-deca ne-1-ol(9b, n=10)

White solid of the title compound (9b, n=10) was obtained by a proceduresimilar to (8-1) (yield 84%).

TLC: (hexane-AcOEt: 7-3) Rf=0.21

¹H NMR (200 M Hz), δ: 1.29(s br, 12H, H-10 to 15), 1.60(m, 4H, H-9,16),2.58(t, J=7.4 Hz, 2H, H-8), 3.64(t, J=6.4 Hz, 2H, H-17) 3.77(s, 3H,H-18), 3.82(s, 3H, H-19), 6.83(d, J=8.9 Hz, 2H, H-3″,5″), 6.88-6.93(m,2H, H-4,6), 7.24(s, 1H, H-2), 7.86(d, J=9.6 Hz, 1H, H-7), 7.75(d, J=8.9Hz, 2H, H-2″,6″)

¹³C NMR (50 M Hz), δ: 24.92(C-15), 25.79(C-9), 28.71(C-8),29.42-29.59(C-10 to 14), 32.85(C-16), 55.63, 55.76(C-18,19),63.10(C-17), 102.31(C-4), 113.20(C-6), 114.31(C-3″,5″), 114.74(C-7),123.56(C-2), 123.95(C-3), 128.92(C-2″,6″), 129.87(C-7′), 130.19(C-3′),132.35(C-1″), 156.31(C-5), 163.58 (C-4″).

(8-3) Production of10-[6-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-deca ne-1-ol(9c, n=10)

White solid of the title compound (9c, n=10) was obtained by a proceduresimilar to (8-1) (yield 80%).

TLC: (hexane-AcOEt: 7-3) Rf=0.21

¹H NMR (300 M Hz), δ: 1.28(s br, 12H, H-10 to 15), 1.58(m, 4H, H-9,16),2.58(t, J=7.3 Hz, 2H, H-8), 3.63(t, J=6.6 Hz, 2H, H-17) 3.78(s, 3H,H-18), 3.87(s, 3H, H-19), 6.85(d, J=8.9 Hz, 2H, H-3″,5″), 6.86(m, 1H,H-5), 7.17(s, 1H, H-2), 7.32(d, J=8.6 Hz, 1H, H-4), 7.52(d, J=2.2 Hz,1H, H-7), 7.77(d, J=8.9 Hz, 2H, H-2″,6″).

¹³C NMR (75 M Hz), δ: 24.89(C-15), 25.70(C-9), 28.81(C-8),29.34-29.52(C-10 to 14), 32.77(C-16), 55.56, 55.78(C-18,19),63.03(C-17), 98.22(C-7), 111.88(C-5), 114.28(C-3″,5″), 119.94(C-4),121.29(C-2), 123.60(C-3), 125.09(C-3′), 128.85(C-2″,6″), 129.84(C-1″),136.39(C-7′), 157.87(C-6), 163.53(C-4″).

(8-4)

The following compounds were produced by procedures similar to (8-1).The yield is shown in Table 2.

-   -   12-[4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-dodecane-1-ol        (9a, n=12),    -   14-[4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-tetradecane-1-ol        (9a, n=14),    -   16-[4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-hexadecane-1-ol        (9a, n=16),    -   18-[4-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-octadecane-1-ol        (9a, n=18),    -   12-[5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-dodecane-1-ol        (9b, n=12),    -   14-[5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-tetradecane-1-ol        (9b, n=14),    -   16-[5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-hexadecane-1-ol        (9b, n=16),    -   18-[5-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-octadecane-1-ol        (9b, n=18),

12-[6-methoxy-1-(4-methoxybenzsulfonyl)-1H-indole-3-yl]-dodecane-1-ol(9c, n=12) TABLE 2 X = —(CH₂)_(n)OH R n Formula MW Yield 9a 4-MeO 10C₂₆H₃₅NO₅S 473.63 93% 12 C₂₈H₃₉NO₅S 501.68 94% 14 C₃₀H₄₃NO₅S 529.73 57%16 C₃₂H₄₇NO₅S 557.79 47% 18 C₃₄H₅₁NO₅S 585.84 50% 9b 5-MeO 10 C₂₆H₃₅NO₅S473.63 84% 12 C₂₈H₃₉NO₅S 501.68 95% 14 C₃₀H₄₃NO₅S 529.73 91% 16C₃₂H₄₇NO₅S 557.79 91% 18 C₃₄H₅₁NO₅S 585.84 94% 9c 6-MeO 10 C₂₆H₃₅NO₅S473.63 80% 12 C₂₈H₃₉NO₅S 501.68 85%

(9-1) Production of 10-(5-methoxy-1H-indole-3-yl)-decane-1-ol (1-1a,n=10)

To the solution of the indole (9b, n=10) (288 mg, 0.61 mmol, 1 eq)obtained in (8-2) in dry methanol (10 mL) were added disodiumhydrogenphosphate (173 mg, 1.22 mmol, 2 eq) and sodium amalgam (6%, 5 g)at 0° C. argon atmosphere. The mixture was stirred at room temperaturefor 12 hours, quenched with saturated solution of ammonium chloride (50mL), and extracted three times with ethyl ether (50 mL). The extractswere combined, washed with aqueous solution of sodium chloride, driedover magnesium sulfate, and concentrated. The resulting concentrate wasapplied to silica gel using hexane-ethyl acetate (80-20) to (75-25) forthe eluate to obtain white crystals of the title compound (1-1a, n=10)(155 mg, yield 84%).

TLC: (hexane-AcOEt: 6-4) Rf=0.38

¹H NMR (200 M Hz), δ: 1.30(s br, 12H, H-10 to 15), 1.57(m, 2H, H-16),1.71(m, 2H, H-9), 2.71(t, J=7.4 Hz, 2H, H-8), 3.64(t, J=6.4 Hz, 2H,H-17), 3.88(s, 3H, H-18), 6.85(dd, J=8.9 Hz, J=2.2 Hz, 1H, H-6), 6.94(s,1H, H-2), 7.05(d, J=2.2 Hz, 1H, H-4), 7.24(d, J=8.9 Hz, 1H, H-7),7.86(s, 1H, H-1)

¹³C NMR (50 M Hz), δ: 25.22 (C-15), 25.79(C-9), 29.48-29.64(C-10 to 14),30.04(C-8), 32.87(C-16), 56.08(C-18), 63.15(C-17), 101.15(C-4), 111.75,111.92(C-6,7), 116.95(C-3), 121.99(C-2), 128.08(C-3′), 131.65(C-7′),153.82(C-5).

(9-2) Production of 10-(4-methoxy-1H-indole-3-yl)-decane-1-ol (1-1b,n=10)

White crystal of the title compound (1-1b, n=10) was obtained by theprocedure similar to (9-1) (yield 85%).

TLC: (hexane-AcOEt: 6-4) Rf=0.43

¹H NMR (300 M Hz), δ: 1.31(s br, 12H, H-10 to 15), 1.57(m, 2H, H-16),1.68(m, 2H, H-9), 2.87(t, J=7.5 Hz, 2H, H-8), 3.64(t, J=6.2 Hz, 2H,H-17), 3.92(s, 3H, H-18), 6.48(d, J=7.8 Hz, 1H, H-5), 6.82(s, 1H, H-2),6.94(d, J=7.8 Hz, 1H, H-7), 7.07(t, J=7.8 Hz, 1H, H-6), 7.88(s, 1H,H-1).

¹³C NMR (75 M Hz), δ: 25.73(C-15), 26.87(C-9), 29.43-29.60(C-10 to 14),31.15(C-8), 32.79(C-16), 55.08(C-18), 63.10(C-17), 99.25(C-7),104.32(C-5), 117.46(C-3), 117.84(C-3′), 119.68(C-6), 122.52(C-2),138.10(C-7′), 155.02(C-4).

(9-3). Production of 14-(4-methoxy-1H-indole-3-yl)-tetradecane-1-ol(1-1b, n=14)

White crystal of the title compound (1-1b, n=14) was obtained by theprocedure similar to (9-1) (yield 99%).

TLC: (hexane-AcOEt: 7-3) Rf=0.25

¹H-NMR (300 M Hz), δ: 1.27(s br, 12H, H-10 to 19), 1.57(m, 2H, H-20),1.68(m, 2H, H-9), 2.86(t, J=7.3 Hz, 2H, H-8), 3.64(t, J=6.4 Hz, 2H,H-21), 3.92(s, 3H, H-22), 6.47(d, J=7.8 Hz, 1H, H-5), 6.82(s, 1H, H-2),6.94(d, J=7.8 Hz, 1H, H-7), 7.07(t, J=7.8 Hz, 1H, H-6), 7.88(s, 1H,H-1).

¹³C NMR (75 M Hz), δ: 25.72(C-19), 26.88(C-9), 29.42-29.69(C-10 to 18),31.18(C-8), 32.80(C-20), 55.07(C-22), 63.10(C-21), 99.23(C-7),104.31(C-5), 117.45(C-3), 117.88(C-3′), 119.65(C-6), 122.52(C-2),138.08(C-7′), 155.02(C-4).

(9-4) Production of 10-(6-methoxy-1H-indole-3-yl)-decane-1-ol (1-1c,n=10)

White crystal of the title compound (1-1c, n=10) was obtained by theprocedure similar to (9-1) (yield 84%).

TLC: (hexane-AcOEt: 7-3) Rf=0.14

¹H NMR (300 M Hz), δ: 1.30(s br, 12H, H-10 to 15), 1.56(m, 2H, H-16),1.69(m, 2H, H-9), 2.71(t, J=7.3 Hz, 2H, H-8), 3.64(m, 2H, H-17), 3.85(s,3H, H-18), 6.79(dd, J=8.6 Hz, J=2.2 Hz, 1H, H-5), 6.85(s, 1H, H-2),6.87(m, 1H, H-7), 7.47(d, J=8.6 Hz, 1H, H-4), 7.81(s, 1H, H-1).

¹³C NMR (75 M Hz), δ: 25.20(C-15), 25.71(C-9), 29.39-29.57(C-10 to 14),30.14(C-8), 32.79(C-16), 55.69(C-18), 63.08(C-17), 94.62(C-7),108.95(C-5), 117.11(C-3), 119.56; 119.71(C-2,4), 122.12(C-3′),137.04(C-7′), 156.37(C-6).

(9-5)

The following indole derivatives (1-1) were produced by proceduressimilar to (9-1). All of these compounds were obtained in the form ofwhite crystals. The yield is shown in Table 3. The analytical data areshown in Tables 4 to 6.

-   -   12-(5-methoxy-1H-indole-3-yl)-dodecane-1-ol (1-1a, n=12),    -   14-(5-methoxy-1H-indole-3-yl)-tetradecane-1-ol (1-1a, n=14),    -   16-(5-methoxy-1H-indole-3-yl)-hexadecane-1-ol (1-1a, n=16),    -   18-(5-methoxy-1H-indole-3-yl)-octadecane-1-ol (1-1a, n=18),    -   12-(4-methoxy-1H-indole-3-yl)-dodecane-1-ol (1-1b, n=12),    -   16-(4-methoxy-1H-indole-3-yl)-hexadecane-1-ol (1-1b, n=16),    -   18-(4-methoxy-1H-indole-3-yl)-octadecane-1-ol (1-1b, n=18),    -   12-(6-methoxy-1H-indole-3-yl)-dodecane-1-ol (1-1c, n=12)    -   14-(6-methoxy-1H-indole-3-yl)-tetradecane-1-ol (1-1c, n=14),

16-(6-methoxy-1H-indole-3-yl)-hexadecane-1-ol (1-1c, n=16) TABLE 3 X =—(CH₂)_(n)OH R n Formula MW Yield 1-1b 4-MeO 10 C₁₉H₂₉NO₂ 303.44 85% 12C₂₁H₃₃NO₂ 331.49 82% 14 C₂₃H₃₇NO₂ 359.55 99% 16 C₂₅H₄₁NO₂ 387.60 92% 18C₂₇H₄₅NO₂ 415.65 96% 1-1a 5-MeO 10 C₁₉H₂₉NO₂ 303.44 84% 12 C₂₁H₃₃NO₂331.49 95% 14 C₂₃H₃₇NO₂ 359.55 87% 16 C₂₅H₄₁NO₂ 387.60 91% 18 C₂₇H₄₅NO₂415.65 85% 1-1c 6-MeO 10 C₁₉H₂₉NO₂ 303.44 84% 12 C₂₁H₃₃NO₂ 331.49 80% 14C₂₃H₃₇NO₂ 359.55 92% 16 C₂₅H₄₁NO₂ 387.60 91%

TABLE 4 R n Analysis 1-1b 4-MeO 10 m.p: 66-67° C. UV (acetonitrile):λ_(max): 225 nm (ε 301465); 270 nm (ε 71091); 283 nm (ε 67263); 293 nm(ε 68010) MS (EI): 303.4(M⁺, 25); 160.3(C₁₀H₁₀NO, 100); 130.4 (C₉H₈N,17) Analysis (%): calculated: C: 75.21, H: 9.63, N: 4.62, O: 10.55found: C: 75.45, H: 9.71, N: 4.54, O: 10.30 12 m.p: 45-46° C. UV(acetonitrile): λ_(max): 226 nm (ε 287495); 270 nm (ε 81272); 283 nm (ε75913); 292 nm (ε 73019) MS (EI): 331.4(M⁺, 32); 160.3(C₁₀H₁₀NO, 100);130.4(C₉H₈N, 16) Analysis (%): calculated: C: 76.09, H: 10.03, N: 4.23,O: 9.65 found: C: 76.02, H: 10.10, N: 4.12, O: 9.76 14 m.p: 48-49° C. UV(acetonitrile): λ_(max): 225 nm (ε 288010); 270 nm (ε 66570); 283 nm (ε62650); 293 nm (ε 60840) MS (EI): 359.5(M⁺, 35); 160.3(C₁₀H₁₀NO, 100);130.4(C₉H₈N, 16) Analysis (%): calculated: C: 76.83, H: 10.37, N: 3.90,O: 8.90 found: C: 77.15, H: 10.52, N: 3.77, O: 8.56 16 m.p: 53-54° C. UV(acetonitrile): λ_(max): 225 nm (ε 295827); 270 nm (ε 68194); 283 nm (ε64214); 293 nm (ε 62969) MS (EI): 387. 5(M⁺, 43); 160.3(C₁₀H₁₀NO, 100);130.3(C₉H₈N, 15) Analysis (%): calculated: C: 77.47, H: 10.66, N: 3.61,O: 8.26 found: C: 77.62, H: 10.76, N: 3.54, O: 8.08 18 m.p: 65-66° C. UV(acetonitrile): λ_(max): 225 nm (ε 290535); 270 nm (ε 69000); 283 nm (ε64861); 293 nm (ε 63535) MS (EI): 415.5(M⁺, 41); 160.3(C₁₀H₁₀NO, 100);130.3(C₉H₈N, 15) Analysis (%): Calculated C: 78.02, H: 10.91, N: 3.37,O: 7.70 found: C: 78.01, H: 10.98, N: 3.29, O: 7.72

TABLE 5 R n Analysis 1-1a 5-MeO 10 m.p: 75-76° C. UV (acetonitrile):λ_(max): 206 nm (ε 209091); 225 nm (ε 218030); 278 nm (ε 57697); 297 nm(ε 45465) MS (EI): 303.4 (M⁺, 25); 160.3 (C₁₀H₁₀NO, 100); 145.3 (C₉H₇NO,7) Analysis (%): calculated: C: 75.21, H: 9.63, N: 4.62, O: 10.55 found:C: 75.59, H: 9.79, N: 4.51, O: 10.11 12 m.p: 82-83° C. UV(acetonitrile): λ_(max): 206 nm (ε 229893); 226 nm (ε 256951); 278 nm (ε77806); 298 nm (ε 58825) MS (EI): 331.4 (M⁺, 28); 160.3 (C₁₀H₁₀NO, 100);145.3 (C₉H₇NO, 6) Analysis (%): calculated: C: 76.09, H: 10.03, N: 4.23,O: 9.65 found: C: 76.43, H: 10.15, N: 4.11, O: 9.31 14 m.p: 87-88° C. UV(acetonitrile): λ_(max): 207 nm (ε 245040); 225 nm (ε 272280); 278 nm (ε84870); 297 nm (ε 64200) MS (EI): 359.5 (M⁺, 35); 160.3 (C₁₀H₁₀NO, 100);145.3 (C₉H₇NO, 6) Analysis (%): calculated: C: 76.83, H: 10.37, N: 3.90,O: 8.90 found: C: 76.86, H: 10.49, N: 3.81, O: 8.84 16 m.p: 92-93° C. UV(acetonitrile): λ_(max): 207 nm (ε 231449); 225 nm (ε 249020); 278 nm (ε78327); 297 nm (ε 58439) MS (EI): 387.5 (M⁺, 35); 160.3 (C₁₀H₁₀NO, 100);145.3 (C₉H₇NO, 5) Analysis (%): calculated: C: 77.47, H: 10.66, N: 3.61,O: 8.26 found: C: 77.76, H: 10.78, N: 3.57, O: 7.89 18 m.p: 94-95° C. UV(acetonitrile): λ_(max): 207 nm (ε 250653); 225 nm (ε 285366); 278 nm (ε94624); 297 nm (ε 70594) MS (EI): 415.5 (M⁺, 38); 160.3 (C₁₀H₁₀NO, 100);145.3 (C₉H₇NO, 5) Analysis (%): Calculated C: 78.02, H: 10.91, N: 3.37,O: 7.70 Found C: 77.88, H: 10.99, N: 3.29, O: 7.84

TABLE 6 R n Analysis 1-1c 6-MeO 10 m.p: 88-89° C. UV (acetonitrile):λ_(max): 206 nm (ε 189323); 228 nm (ε 279970); 275 nm (ε 56545); 292 nm(ε 57990) MS (EI): 303.3 (M⁺, 31); 160.3 (C₁₀H₁₀NO, 100); 145.3 (C₉H₇NO,8) Analysis (%): calculated: C: 75.21, H: 9.63, N: 4.62, O: 10.55 found:C: 75.51, H: 9.80, N: 4.48, O: 10.21 12 m.p: 95-96° C. UV(acetonitrile): λ_(max): 204 nm (ε 165544); 229 nm (ε 252631); 276 nm (ε39748); 294 nm (ε 44272) MS (EI): 331.4 (M⁺, 32); 160.3 (C₁₀H₁₀NO, 100);145.3 (C₉H₇NO, 7) Analysis (%): calculated: C: 76.09, H: 10.03, N: 4.23,O: 9.65 found: C: 76.31, H: 10.16, N: 4.17, O: 9.36

Example 2 (1) Production oftert-butyl-hexadecane-15-ynyloxy-dimethylsilane (13a)

The solution of (14-bromo-tetradecyloxy)-tert-butyl-dimethylsilane (8.9g, 21.4 mmol, 1 eq) in DMSO (10 mL) was added dropwise to the solutionof N,N-diethylethane-1,2-diamine lithium acetylide (3.1 g, 33.2 mmol,1.5 eq) in DMSO (15 mL) at 0° C. This solution was stirred at roomtemperature for 6 hours, poured into saturated aqueous solution ofpotassium chloride (100 mL), and extracted three times with hexane (100mL). The extract was washed with aqueous solution of sodium chloride,dried over magnesium sulfate, and concentrated. The resultingconcentrate was subjected to silica gel flush column chromatography(eluate: hexane-CH₂Cl₂=80-20) to obtain the colorless liquid of thetitle compound (6.12 g, yield 81%).

MW: (C₂₂H₄₄OSi) 352.67.

TLC: (hexane-CH₂Cl₂: 9-1) Rf=0.38.

¹H NMR (300 M Hz, CDCl₃), δ: 0.04(s, 6H, H-17,18), 0.90(s, 9H,H-20,21,22), 1.25-1.55(m, 24H, H-3 to 13), 1.93(t, J=2.5 Hz, 1H, H-16),2.15(td, J=7.0 Hz, J=2.7 Hz, 2H, H-14), 3.59(t, J=6.6 Hz, 2H, H-1).

¹³C NMR (75 M Hz, CDCl₃), δ: −5.28 (C-17, 18), 18.38 (C-14),18.41(C-19), 25.96(C-20,21,22), 28.48-29.61(C-3 to 13), 32.86(C-2),63.33(C-1), 67.98(C-16), 84.80 (C-15).

(2-1) Production of tert-butyl (2-iodo-3-methoxyphenyl)-carbamate (16a)

To the solution of tert-butyl (3-methoxyphenyl)-carbamate (5 g, 22.4mmol, 1 eq) in dry diethyl ether (50 mL) was added pentane solution oft-BuLi (35 mL, 49.3 mmol, 2.2 eq) at −20° C., and the mixture wasstirred at 3 hours. To this mixed solution was added the solution ofiodine (6.83 g, 26.9 mmol, 1.2 eq) in diethylether (60 mL) at −78° C.,and after heating the whole solution to room temperature, the solutionwas stirred for20 hours. After adding saturated aqueous solution ofNa₂S_(2O) ₃ (100 mL), the mixture was extracted three times with diethylether (100 mL). The extract was washed with aqueous solution of sodiumchloride, dried over magnesium sulfate, and concentrated under reducedpressure. The resulting concentrate was applied to silica gel (eluate:hexane-AcOEt=90-10) to give white solid of the title compound (5.755 g,yield 74%).

MW: (C₁₂H₁₆INO₃) 349.17.

TLC: (hexane-AcOEt: 8-2) Rf=0.59.

m.p.: 69-71° C.

¹H NMR (300 M Hz, CDCl₃), δ: 1.53(s, 9H, H-11,12,13), 3.88(s, 3H, H-7),6.53 (dd, J=8.4 Hz, J=1.3 Hz, 1H, H-6), 7.04(s, 1H, H-8) 7.25(td, J=8.4Hz, J=0.4 Hz, 1H, H-5), 7.73(dd, J=8.4 Hz, J=1.3 Hz, 1H, H-4).

¹³C NMR (75 M Hz, CDCl₃), δ: −28.3(C-11,12,13), 56.5(C-7), 80.95(C-10),90.10(C-2), 105.40(C-4), 112.5(C-6), 129.63(C-5), 13.76(C-1),153.39(C-3), 158.23(C-9).

(2-2) Production of tert-butyl (2-iodo-6-methoxyphenyl)-carbamate (16b)

The title compound (16b) was obtained by a procedure similar to (2-1)(yield 46%).

(2-3) Production of tert-butyl (2-iodo-4-methoxyphenyl)-carbamate (16c)

The title compound (16c) was obtained by a procedure similar to (2-1)(yield 26%).

(3-1) Production of tert-butyl{2-[16-(tert-butyl-dimethylsilanoxy)-hexadecane-1-ynyl]-4-methoxyphenyl}-carbamate(17a, n=14)

A mixture of tert-butyl-hexadecane-15-ynyloxy-dimethylsilane (757 mg,2.15 mmol, 1.5 eq), tert-butyl (2-iodo-4-methoxyphenyl)carbamate (500mg, 1.43 mmol, 1 eq), [Pd(PPh₃)₂Cl₂] (45 mg, 0.064 mmol, 0.05 eq), CuI(12 mg, 0.064 mmol, 0.05 eq), and Et₃N(5 mL) was refluxed for 24 hours.Water (50 mL) and AcOEt (60 mL) were added to the reaction mixture, andthe solution was filtered through celite. The filtrate was extractedthree times with AcOEt (100 mL). The extract was washed with aqueoussolution of sodium chloride, dried over magnesium sulfate, andconcentrated under reduced pressure. The resulting concentrate wassubjected to silica gel flush chromatography (eluate: hexane-AcOEt=98-2)to obtain pale yellow liquid of the title compound (754 mg, yield 92%).

MW: (C₃₄H₅₉NO₄Si) 573.92.

TLC: (hexane-AcOEt: 9-1) Rf=0.49.

¹H NMR (300 M Hz, CDCl₃), δ: 0.04(s, 6H, H-30,31), 0.89(s, 9H,H-33,34,35), 1.26-1.70(m, 24H, H-17 to 28), 1.50(s, 9H, H-32,33,34),2.48(t, J=6.9 Hz, 2H, H-16), 3.59(t, J=6.6 Hz, 2H, H-29), 3.76(s, 3H,H-7), 6.81(m, 2H, H-3,5), 7.07(s, H-8), 7.96(d, J=8.8 Hz, 1H, H-6)

¹³C NMR (75 M Hz, CDCl₃), δ: −5.28(C-30,31), 18.35(C-32), 19.55(C-16),25.78(C-33,34,35), 25.96(C-27), 28.34-29.64(C-17 to C-26), 32.87(C-28),55.52(C-7), 63.32(C-29), 76.05(C-14), 80.29(C-10), 97.29(C-15), 115.01(C-5), 116.06(C-6), 118.96(C-3), 133.12(C-1), 152.69(C-4), 154.32(C-9).

(3-2)

The following compounds were produced by procedures similar to (3-1).The yield is shown in Table 7.

-   -   tert-butyl        {2-[18-(tert-butyl-dimethylsilanoxy)-octadecane-1-ynyl]-4-methoxyphenyl}-carbamate        (17a, n=16),    -   tert-butyl        {2-[16-(tert-butyl-dimethylsilanoxy)-hexadecane-1-ynyl]-3-methoxyphenyl}-carbamate        (17b, n=14),    -   tert-butyl        {12-[18-(tert-butyl-dimethylsilanoxy)-octadecane-1-ynyl]-3-methoxyphenyl}-carbamate        (17b, n=16),    -   tert-butyl        {2-[16-(tert-butyl-dimethylsilanoxy)-hexadecane-1-ynyl]-6-methoxyphenyl}-carbamate        (17c, n=14)

tert-butyl{2-[18-(tert-butyl-dimethylsilanoxy)-octadecane-1-ynyl]-6-methoxyphenyl}-carbamate(17c, n=16) TABLE 7 Y = —(CH₂)_(n)OH R n Yield 17a 4-MeO 14 92% 16 90%17b 3-MeO 14 75% 16 61% 17c 6-MeO 14 57% 16 37%

(4-1) Production of 14-(5-methoxy-l1-indole-2-yl)-tetradecane-1-ol(1-2a, n=14)

A mixture of 1M THF solution of TBAF (5.1 mL, 5.11 mmol, 15 eq) andtert-butyl {2-[16-(tert-butyl-dimethylsilanoxy)-hexadecynyl]-4-methoxyphenyl}-carbamate (195 mg, 0.34 mmol, 1 eq) was refluxed for 24 hours.After removing THF, the residue was diluted with 50 mL of water, andextracted three times with AcOEt (50 mL). The extract was washed withaqueous solution of sodium chloride, dried over magnesium sulfate, andconcentrated. The resulting concentrate was subjected to silica gelflush chromatography (eluate: hexane-AcOEt=70-30) to give white solid ofthe title compound (79.1 mg, yield 81%).

MW: (C₂₃H₃₇NO₂) 359.55.

TLC: (hexane-AcOEt: 7-3) Rf=0.3.

m.p.: 68-69° C.

¹H NMR (300 M Hz, CDCl₃), δ: 1.26(s br, 20H, H-10 to 19), 1.52-1.72(m,4H, H-9,20), 2.72(t, J=7.4 Hz, 2H, H-8), 3.64 (t, J=6.6 Hz, 2H, H-21),3.84(s, 3H, H-22), 6.16(s, 1H, H-3), 6.77(dd, J=8.8 Hz, J=2.2 Hz, 1H,H-6), 7.0(d, J=2.2 Hz, 1H, H-4), 7.17(d, J=8.8 Hz, 1H, H-7), 7.78(s, 1H,H-1)

¹³C NMR (75 M Hz, CDCl₃), δ: 25.71(C-19), 28.35(C-8), 29.22-29.58(C-9 to18), 32.79(C-20), 55.90(C-22), 63.08(C-21), 99.33(C-3), 101.99(C-6),110.67(C-7), 110.83(C-4), 129.31(C-3′), 130.90(C-7′), 140.89(C-2),154.07(C-5).

analysis (%): calculated in terms of C₂₃H₃₇NO₂: C=76.83; H=10.37; N=3.9.

found: C=76.99; H=10.51; N=3.82.

MS: 359.3 (M⁺, 63), 173.9 (C₁₁H₁₃NO,66), 160.1 (C₁₀H₁₁NO, 100) UV:(acetonitrile): λ_(max) 219 nm (ε 25575), 294 nm (ε 6951), 306 nm (ε4292).

(4-2)

The following indole derivatives (1-2) were obtained by proceduressimilar to (4-1). The yield is shown in Table 8.

16-(5-methoxy-1H-indole-2-yl)-hexadecane-1-ol (1-2a, n=16)

MW: (C₂₅H₄₁NO₂) 387.60

TLC: (hexane-AcOEt: 7-3) Rf=0.29.

¹H NMR (300 M Hz, CDCl₃), δ: 1.26 (s br, 24H,H-10to21), 1.52-1.72(m, 4H,H-9,22), 2.72(t, J=7.4 Hz, 2H, H-8), 3.64(t, J=6.6 Hz, 2H, H-23),3.84(s, 3H, H-24), 6.16(s, 1H, H-3), 6.76(dd, J=8.8 Hz, J=2.2 Hz, 1H,H-6), 7.01(d, J=2.2 Hz, 1H, H-4), 7.17(d, J=8.8 Hz, 1H, H-7), 7.77(s,1H, H-1).

¹³C NMR (75 M Hz, CDCl₃), δ: 25.71(C-21), 28.35(C-8), 29.22-29.58(C-9 to20), 32.79(C-22), 55.90(C-24), 63.08(C-23), 99.33(C-3), 101.99(C-6),110.67(C-7), 110.83(C-4), 129.31(C-3′), 130.90(C-7′), 140.89(C-2),154.07(C-5).

analysis (%): calculated in terms of C₂₅H₄₁NO₂: C=77.47; H=10.66;N=3.61.

found: C=77.64; H=10.84; N=3.43.

14-(4-methoxy-1H-indole-2-yl)-tetradecane-1-ol (1-2b, n=14)

MW: (C₂₃H₃₇NO₂) 359.55

TLC: (hexane-AcOEt: 7-3) Rf=0.37.

¹H NMR (300 M Hz, CDCl₃), δ: 1.26(s br, 20H, H-10 to 19), 1.52-1.75(m,4H, H-9,20), 2.73(t, J=7.6 Hz, 2H, H-8), 3.64(t, J=6.9 Hz, 2H, H-21),3.95(s, 3H, H-22), 6.33(s, 1H, H-3), 6.50(d, J=7.9 Hz, 1H, H-5), 6.93(d,J=7.9 Hz, 1H, H-7), 7.04 (t, J=7.9 Hz, 1H, H-6) 7.91(s, 1H, H-1).

¹³C NMR (75 M Hz, CDCl₃), δ: 25.71(C-19), 28.18(C-8), 29.19-29.59(C-9 to18), 32.79(C-20), 55.29(C-22), 63.10(C-21), 96.46(C-3), 99.58 (C-7),103.86(C-5), 119.14 (C-3′), 121.59(C-6) 137.10(C-7′), 138.45(C-2),152.59(C-4).

analysis (%): calculated in terms of C₂₃H₃₇NO₂: C=76.83; H=10.37; N=3.9.

found: C=76.90; H=10.45; N=3.79.

16-(4-methoxy-1H-indole-2-yl)-hexadecane-1-ol (1-2b, n=16)

MW: (C₂₅H₄₁NO₂) 387.60

TLC: (hexane-AcOEt: 7-3) Rf=0.37.

¹H NMR (300 M Hz, CDCl₃), δ: 1.25(s br, 24H, H-10to21), 1.52-1.73(m, 4H,H-9,22), 2.73(t, J=7.6 Hz, 2H, H-8), 3.64(t, J=6.9 Hz, 2H, H-23),3.94(s, 3H, H-24), 6.33(s, 1H, H-3), 6.50(d, J=7.9 Hz, 1H, H-5), 6.93(d,J=7.9 Hz, 1H, H-7), 7.03(t, J=7.9 Hz, 1H, H-6), 7.89(s, 1H, H-1).

¹³C NMR (75 M Hz, CDCl₃), δ: 25.72(C-21), 28.18(C-8), 29.19-29.62(C-9 to20), 32.79(C-22), 55.29(C-24), 63.10(C-23), 96.47(C-3), 99.58(C-7),103.85(C-5), 119.14(C-3′), 121.59(C-6), 137.11(C-7′), 138.45(C-2),152.59(C-4).

analysis (%): calculated in terms of C₂₅H₄₁NO₂: C=77.47; H=10.66;N=3.61.

found: C=77.40; H=10.82; N=3.46.

14-(7-methoxy-1H-indole-2-yl)-tetradecane-1-ol (1-2c, n=14)

MW: (C₂₃H₃₇NO₂) 359.55

TLC: (hexane-AcOEt: 7-3) Rf=0.48.

¹H NMR (300 M Hz, CDCl₃), δ: 1.26(s br, 20H, H-10to 19), 1.52-1.73(m,4H, H-9,20), 2.74(t, J=7.7 Hz, 2H, H-8), 3.64(t, J=6.6 Hz, 2H, H-21),3.95(s, 3H, H-22), 6.21(s, 1H, H-3), 6.58(d, J=7.8 Hz, 1H, H-6), 6.98(t,J=7.8 Hz, 1H, H-5), 7.14(d, J=7.8 Hz, 1H, H-4), 8.12(s, 1H, H-1).

¹³C NMR (75 M Hz, CDCl₃), δ: 25.72(C-19), 28.05(C-8), 28.88-29.59(C-9 to18), 32.79(C-20), 55.21(C-22), 63.09(C-21), 99.75(C-3), 101.07(C-6),112.63(C-4), 119.80(C-5), 122.58(C-3′), 130.08(c-7′), 139.60(C-2),145.50(C-7).

analysis (%): calculated in terms of C₂₃H₃₇NO₂: C=76.83; H=10.37; N=3.9.

found: C=75.51; H=10.30; N=3.40.

16-(7-methoxy-1H-indole-2-yl)-hexadecane-1-ol (1-2c, n=16)

MW: (C₂₅H₄₁NO₂) 387.60

TLC: (hexane-AcOEt: 7-3) Rf=0.49.

¹H NMR (300 M Hz, CDCl3), δ: 1.26(s br, 24H, H-10to21), 1.52-1.73(m, 4H,H-9,22), 2.74(t, J=7.7 Hz, 2H, H-8), 3.64(t, J=6.6 Hz, 2H, H-23),3.95(s, 3H, H-24), 6.20(s, 1H, H-3), 6.58(d, J=7.8 Hz, 1H, H-6), 6.98(t,J=7.8 Hz, 1H, H-5), 7.14(d, J=7.8 Hz, 1H, H-4) 8.13(s, 1H, H-1).

¹³C NMR (75 M Hz, CDCl3), δ: 25.72(C-21), 28.23(C-8), 29.27-29.61(C-9 to20), 32.79(C-22), 55.24(C-24), 63.09(C-23), 99.76(C-3), 101.04(C-6),112.62(C-4), 119.80(C-5), 122.59(C-3′), 130.06(C-7′), 139.62(C-2),145.52(C-7).

analysis (%): calculated in terms of C₂₅H₄₁NO₂: C=77.47; H=10.66;N=3.61.

found: C=77.65; H=10.92; N=3.32. TABLE 8 Y = —(CH₂)_(n)OH R n Yield 1-2a5-MeO 14 81% 16 77% 1-2b 4-MeO 14 84% 16 76% 1-2c 7-MeO 14 66% 16 58%

Test Example 1

Neural stem cell was produced from ES cell in accordance with the methodof Weiss and Reynolds (1996). More specifically, striate body wasextirpated from mouse embryo, and the cells were dispersed in a culturemedium containing EGF (20 ng/mL). The cells were cultured under theconditions of 5% CO₂ and 37° C. for 5 days. The culture was thencentrifuged at 400 rpm in Dissociation Medium (manufactured by Sigma)for 5 minutes, and neurospheres which are cluster of the neural stemcells were obtained. The neurospheres were dispersed in the culturemedium, and cultivation was conducted under the same conditions toproduce secondary neurospheres.

A sterilized cover glass was placed in the well of 24 well plate,treated overnight with polyornithine solution (30 μg/mL), and washedthree times with phosphate buffered saline. Neurospheres were inoculatedon the cover glass at 20 to 50 cells/cover glass. The test compound thathas been adjusted to the concentration of 10⁻⁶M with ethanol was appliedto the cover glass, and the cultivation was continued for a periodsufficient for differentiation of the neurospheres (typically 24 hours).The indole derivatives obtained in the Examples were used for the testcompounds, and the control cells were cultivated without using such testcompound.

Sufficiently differentiated neurospheres were fixed with 4%p-formaldehyde, washed with phosphate buffered saline, and after addingTriton-X100, washed again with phosphate buffered saline. Anti-MAP2(2a+2b) (Sigma) which is a mouse monoclonal antibody used for labelingneurons and Anti-04 (Boeringher) which is a mouse monoclonal antibodyused for labeling oligodendrocytes, and Anti-GFAP (DAKO) which is arabbit monoclonal antibody used for labeling astrocytes were added, andthe cultivation was continued at room temperature for 1 hour orovernight at 4° C. Anti-mouse IgM antibody and fluorescence indicatorwere added, and cultivation was continued at room temperature for 1hour. After washing with phosphate buffered saline, the cover glass wasplaced on a confocal microscope to observe the differentiation of theneurospheres. The results are shown in Table 9. TABLE 9 Percentage X = Y= of neuron Induction —(CH₂)_(n)OH —(CH₂)_(n)OH in relation of differ- Rn n to control entiation Control 100 + 1-1b 4-MeO 16 133 + 1-1a 5-MeO 14143 ++ 16 168 ++ 18 169 ++ 1-1c 6-MeO 16 135 ++ 18 156 ++ 1-2a 4-MeO 16135 ++ 1-2b 5-MeO 14 147 ++ 16 184 ++ 1-2c 7-MeO 16 128 +

The results shown in Table 9 confirm that the indole derivative (1) ofthe present invention has the action of inducing differentiation of theneurospheres which are clusters of neural stem cells into neurons.

INDUSTRIAL APPLICABILITY

The indole derivative (1) of the present invention has the action ofinducing differentiation of neural stem cell specifically into neuron,and this indole derivative is useful as a prophylactic or therapeuticdrug for brain dysfunction (e.g. dementia of the Alzheimer type andParkinson's disease) or neuropathy (e.g. motor paralysis) caused by lossor degeneration of the neuron, and as an agent for promotingdifferentiation of the stem cell.

1. An indole derivative represented by the following general formula(1):

wherein at least one of R¹, R², R³ and R⁴ represents an alkoxy groupcontaining 1 to 20 carbon atoms, and other groups of the R¹, R², R³, andR⁴ represent hydrogen, an alkyl group containing 1 to 6 carbon atoms,acetyl group, or hydroxyl group; and either one of X and Y represents—(CH₂)_(n)OH wherein n is an integer of 0 to 30, and the other one ofthe X and Y represents hydrogen atom; or a salt thereof.
 2. The indolederivative or its salt according to claim 1 wherein one of R¹, R², R³,an R⁴ is an alkoxy group containing 1 to 10 carbon atoms; and othergroups of the R¹, R ², R³, and R⁴ are hydrogen; and n is 10 to
 20. 3. Adrug containing the indole derivative or its salt of claim 1 or 2 as itseffective component.
 4. The drug according to claim 3 wherein the drugis a prophylactic or therapeutic drug for brain dysfunction orneuropathy.
 5. An agent for promoting differentiation of a stem cell,comprising the indole derivative or its salt of claim 1 or 2 as itseffective component.
 6. A pharmaceutical composition comprising theindole derivative or its salt of claim 1 or 2 and a pharmaceuticallyacceptable carrier.
 7. A method for treating brain dysfunction orneuropathy wherein the indole derivative or its salt of claim 1 or 2 isadministered.
 8. Use of the indole derivative or its salt of claim 1 or2 for producing a drug.